CN104090083A - Detection method for in-vitro hemolytic activity of chemical medicine - Google Patents
Detection method for in-vitro hemolytic activity of chemical medicine Download PDFInfo
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Abstract
The invention discloses a detection method for the in-vitro hemolytic activity of a chemical medicine. The detection method is characterized by comprising the following steps of (1) adding red blood cell suspension and normal saline to a test sample in sequence, uniformly mixing the red blood cell suspension and the normal saline with the test sample, taking a mixture of the red blood cell suspension and the normal saline as a negative contrast, and taking a mixture of the red blood cell suspension and deionized water as a positive contrast; and (2) performing inoculation and observation under an environment with the temperature of 37+/-0.5 DEG C. The detection method disclosed by the invention is used for detecting the hemolytic activity of the test sample, so that the complete hemolysis of blood cells can be observed within short time in the positive contrast, and the reliable positive contrast is really constructed; however, no hemolysis or cell aggregation phenomenon is generated in the negative contrast; therefore, an accurate detection result of the hemolytic activity of the test sample can be obtained.
Description
Technical field
The invention belongs to drug safety and detect assessment technique field, be specifically related to the detection method of the external hemolytic of a kind of chemicals.
Background technology
Haemolysis (Hemolysis) is erythrocyte fragmentation, and the phenomenon that haemoglobin is overflowed, can be caused by multiple chemical factors and toxin.In vitro, vibration as powerful in hypotonic solution, mechanicalness, suddenly cryogenic freezing (20 DEG C～-25 DEG C) or thaw suddenly, peracid or cross alkali, and alcohol, ether, soap alkali, choline salt etc. all can cause haemolysis.In vivo, haemolysis can be that hemolytic bacterium or some snake venom are invaded, antigen-antibody reaction (as the blood of input blood grouping in compatability), various mechanical injuries, red blood cell inherence (film, enzyme) defect, some drugs etc. cause.
Hemolytic refers to the reaction such as haemolysis and red blood cell condensation that pharmaceutical preparation causes.Hemolytic reaction comprises immune hemolysis and non-immunity haemolysis.Immune hemolysis is that medicine produces by immune response the haemolysis that antibody causes, is II type and the allergic reaction of III type; Non-immunity haemolysis comprises that medicine is that oxidative hemolysis and the pharmaceutical preparation that risk factor causes causes the reaction such as haemolysis and red blood cell condensation that the change of blood stable state occurs.Every injection and may cause that the other drug preparation of immune hemolysis or non-immunity hemolytic reaction all should carry out hemolytic test.Current hemolytic test is generally carried out according to " chemicals pungency, anaphylaxis and the hemolytic investigative technique governing principle " that come into force in March, 2005, and calculate hemolysis rate.The computing method of hemolysis rate are: centrifugal by hatching test tube after 3 hours, remove supernatant, select the wavelength of 545nm, taking distilled water as blank pipe, adopt spectrophotometer to read the OD value of each pipe, the computing formula of hemolysis rate is as follows: hemolysis rate=(OD Shi Yan Guan – OD negative control pipe)/(OD positive control Guan – OD negative control pipe) % shows to have haemolysis to occur in the time that hemolysis rate is greater than 5%.
But, in the process of practical application, find, method in this governing principle has certain limitation, such as the positive control in the method can't make haemocyte haemolysis within observing time complete, and from the computing formula of hemolysis rate, only have in the time that 100% haemolysis occurs positive control pipe, whether evaluation test pipe there is haemolysis objectively.Therefore, existing methodical positive control is because of haemolysis incomplete, and it has just lost the meaning as positive control to a certain extent, makes the testing result of tested tested material not accurate enough.
Summary of the invention
Technical matters to be solved by this invention is incomplete for positive control haemolysis in the detection method of the external hemolytic of existing chemicals, may cause the not accurate enough defect of testing result of tested tested material, and a kind of detection method of the new external hemolytic of chemicals is provided.Detect the hemolytic of tested material with method of the present invention, can make positive control observe haemocyte haemolysis within a short period of time complete, really set up reliable positive control, and negative control occurs without haemolysis or cell condensation phenomenon, thereby obtain the testing result of the hemolytic of tested material more accurately.
The invention provides following technical proposals solves the problems of the technologies described above.
Technical scheme provided by the invention is: the detection method of the external hemolytic of a kind of chemicals, it comprises the steps:
(1) after adding successively erythrocyte suspension and physiological saline in tested material sample, mix, get the potpourri of erythrocyte suspension and physiological saline as negative control simultaneously, get the potpourri of erythrocyte suspension and deionized water as positive control;
Under (2) 37 DEG C ± 0.5 DEG C environment, hatch and observe;
In step (1), in the operation at the described potpourri of getting erythrocyte suspension and physiological saline as negative control, the volume ratio of described erythrocyte suspension and described physiological saline is 1: 1.25～1.3; In operation at the described potpourri of getting erythrocyte suspension and deionized water as positive control, the volume ratio of described erythrocyte suspension and described deionized water is 1: 1.25～1.3.
In the present invention, in operation at the described potpourri of getting erythrocyte suspension and deionized water as positive control, the volume ratio of described erythrocyte suspension and described deionized water is 1: 1.25 o'clock, buffer system cumulative volume increases by 12.5%, the volume ratio of described erythrocyte suspension and described deionized water is 1: 1.3 o'clock, buffer system cumulative volume increases by 15%, all in generally acknowledged ± 15% scope (toxicology test volumetric errors scope be known as ± 15%).
In the present invention, described chemicals is the various kinds of drug that need to carry out hemolytic detection of the conventional indication in this area, comprises the chemicals of intravascular method administration or non-intravascular method administration.Conventional the same with this area, unless otherwise specified, the clinical injection for non-intravascular method administration, with the clinical working concentration of each medicine operation instructions regulation, after diluting at 1: 3 with physiological saline as need testing solution; The clinical working concentration specifying using operation instructions for the injection of intravascular administration is as need testing solution.
In step (1), described tested material sample, as described in the routine of this area, coordinates the follow-up erythrocyte suspension adding and physiological saline to make tested material form several concentration gradients as chosen several volumes according to the governing principle of mentioning in " chemicals pungency, anaphylaxis and the hemolytic investigative technique governing principle " that come into force in March, 2005; Meanwhile, choose corresponding erythrocyte suspension and the volume of physiological saline, the cumulative volume of the sample mix liquid of each concentration gradient is consistent; In addition, negative control and positive control also comprise the erythrocyte suspension of same volume and physiological saline or the deionized water of respective volume, to keep consistent with the cumulative volume of sample mix liquid.Preferably, in described adding successively in the operation mixing after erythrocyte suspension and physiological saline in tested material sample, described tested material sample comprises 5 volumes, be respectively X, 2X, 3X, 4X and 5X, the volume of described physiological saline respectively is 30.25X, 29.25X, 28.25X, 27.25X and 26.25X, and the volume of described erythrocyte suspension is 25X; In operation at the described potpourri of getting erythrocyte suspension and physiological saline as negative control, the volume of described erythrocyte suspension is 25X, and the volume of described physiological saline is 31.25X; In operation at the described potpourri of getting erythrocyte suspension and deionized water as positive control, the volume of described erythrocyte suspension is 25X, the volume of described deionized water is 31.25X, described X can be any specific volume, as long as it conveniently carries out conventional hemolytic experiment.
In step (1), the concentration of described erythrocyte suspension can be the concentration of this area routine for the erythrocyte suspension of hemolytic detection, is preferably 2%, and described number percent is the percent by volume that blood accounts for erythrocyte suspension.Conventional with this area, described 2% erythrocyte suspension can be prepared by the following method: get several milliliters of rabbit blood (or sheep blood), put into containing the Erlenmeyer flask jolting of beaded glass 10 minutes, or stir blood with glass bar, remove fibrinogen, make into defibrinated blood; Add approximately 10 times of amounts of 0.9% sodium chloride solution, shake up, centrifugal 15 minutes of 1000-1500r/min, removes supernatant, and the red blood cell of precipitation washs 2-3 time as stated above with 0.9% sodium chloride solution again, till the not aobvious redness of supernatant; Gained red blood cell is made into 2% suspension with 0.9% sodium chloride solution, is for experiment.In the present invention, described erythrocyte suspension is preferably for taking from the erythrocyte suspension of rabbit.
In step (1), described physiological saline is as described in the routine of this area.In the present invention, refer to general mammal physiological saline, it is 0.9% sodium-chloride water solution, its osmotic pressure value and normal person's blood plasma, tissue fluid are all much the same, so can be used as fluid infusion (can not reduce and increase Na ion concentration in normal human) and other medical applications, also be commonly used in vitro culture living tissue, cell.Described physiological saline generally can be prepared and obtain by the following method: take 0.9 gram of sodium chloride, be dissolved in a small amount of distilled water, be diluted to 100 milliliters.
In step (2), preferably, described incubation temperature is 37 DEG C.
In step (2), the described haemolysis situation of observing at regular intervals tested material sample mix liquid, positive control and negative control in the process of hatching that is viewed as.Preferably, described in be viewed as the 1st hour that hatches every 15 minutes observe 1 time, after 1 hour, every 1 hour observe 1 time.In general, hatch 3 hours, observe 3 hours.
The judgment principle of described haemolysis situation is conventional according to this area, as carried out according to the governing principle of mentioning in " chemicals pungency, anaphylaxis and the hemolytic investigative technique governing principle " that come into force in March, 2005, when negative control occurs without haemolysis and cohesion, when positive control has haemolysis to occur, if haemolysis and cohesion did not occur tested material solution in 3 hours, tested material can be injected use; If haemolysis and (or) cohesion occurred tested material solution in 3 hours, tested material should not be injected use.
For the judgement of described haemolysis and cohesion, can carry out according to following principle: if the solution in test is clear and bright redness, and acellular residual or have a small amount of red blood cell residual, show to have haemolysis to occur; As red blood cell all sinks, supernatant liquid achromatism and clarity, shows to occur without haemolysis.If have brownish red or rufous flocculent deposit in solution, after jolting, do not disperse, show to have red blood cell condensation to occur.If any the phenomenon of red blood cell condensation, can further judge by the following method true cohesion or pseudo agglutination.If condensation product can be uniformly dispersed again after vibration, or condensation product is placed on microslide, drip 2 0.9% sodium chloride solutions at cover glass edge, put micro-Microscopic observation, cohesion red blood cell can be pseudo agglutination by the person of breaking up, if condensation product is not shaken loose or is not true cohesion by the person of breaking up on slide.
Judgement for described haemolysis is more preferably carried out with following method: hemolytic experiment carries out in test tube, centrifugal by hatching test tube after 3 hours, remove supernatant, select the wavelength of 545nm, taking distilled water as blank pipe, adopt spectrophotometer to read the OD value of each pipe, the computing formula of hemolysis rate is as follows: hemolysis rate=(OD Shi Yan Guan – OD negative control pipe)/(OD positive control Guan – OD negative control pipe) % shows to have haemolysis to occur in the time that hemolysis rate is greater than 5%; If haemolysis and cohesion did not occur tested material solution in 3 hours, tested material can be injected use; If haemolysis and (or) cohesion occurred tested material solution in 3 hours, tested material should not be injected use.
Meeting on the basis of this area general knowledge, above-mentioned each optimum condition, can combination in any, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material be commercially available obtaining all.
Positive progressive effect of the present invention is: the hemolytic that detects tested material with method of the present invention, can make positive control observe haemocyte haemolysis within a short period of time complete, really set up reliable positive control, and negative control occurs without haemolysis or cell condensation phenomenon, thereby obtain the testing result of the hemolytic of tested material more accurately.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to conventional method and condition, or selects according to catalogue.
In following embodiment, red cell suspension used is the erythrocyte suspension of taking from rabbit.Described erythrocyte suspension is prepared by the following method: get rabbit blood number milliliter, put into containing the Erlenmeyer flask jolting of beaded glass 10 minutes, or stir blood with glass bar, remove fibrinogen, make into defibrinated blood; Add approximately 10 times of amounts of 0.9% sodium chloride solution, shake up, centrifugal 15 minutes of 1000-1500r/min, removes supernatant, and the red blood cell of precipitation washs 2-3 time as stated above with 0.9% sodium chloride solution again, till the not aobvious redness of supernatant; Gained red blood cell is made into 2% suspension with 0.9% sodium chloride solution, is for experiment.
In following embodiment, tested material used is Fleroxacin injection.
Embodiment 1
1, get 7 test tubes, number respectively 1～7.Wherein, 1～5 is tested material sample hose, 6 negative control tube, and 7 positive control tube, add respective reaction thing by table 1 respectively.
Table 1
| Test tube numbering | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 2% red cell suspension (ml) | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 |
| Physiological saline (ml) | 2.625 | 2.725 | 2.825 | 2.925 | 3.025 | 3.125 | ? |
| Distilled water (ml) | ? | ? | ? | ? | ? | ? | 3.125 |
| Tested material (ml) | 0.5 | 0.4 | 0.3 | 0.2 | 0.1 | ? | ? |
2, test tube 1～7 is placed in to 37 DEG C and hatches 3 hours, hatch after 3 hours, adopt ADVIA2120 type automatic blood analyzer to detect erythrocytic number in positive control pipe.Found that: No. 7 pipes (positive control pipe) have no red blood cell, and haemolysis is complete, and its Cytometric concrete outcome is in table 2.
Table 2
| Test tube numbering | 6 | 7 |
| 2% red cell suspension (ml) | 2.5 | 2.5 |
| Physiological saline (ml) | 3.125 | ? |
| Deionized water (ml) | 0 | 3.125 |
| Red blood cell count(RBC) (10 12/L) | 0.09 | 0 |
Embodiment 2
1, get 7 test tubes, number respectively 1～7.Wherein, 1～5 is tested material sample hose, 6 negative control tube, and 7 positive control tube, add respective reaction thing by table 3 respectively.
Table 3
| Test tube numbering | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 2% red cell suspension (ml) | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 |
| Physiological saline (ml) | 2.75 | 2.85 | 2.95 | 3.05 | 3.15 | 3.25 | ? |
| Distilled water (ml) | ? | ? | ? | ? | ? | ? | 3.25 |
| Tested material (ml) | 0.5 | 0.4 | 0.3 | 0.2 | 0.1 | ? | ? |
2, test tube 1～7 is placed in to 37 DEG C and hatches 3 hours, hatch after 3 hours, adopt ADVIA2120 type automatic blood analyzer to detect erythrocytic number in positive control pipe.Found that: No. 7 pipes (positive control pipe) have no red blood cell, and haemolysis is complete, and its Cytometric concrete outcome is in table 4.
Table 4
Comparative example 1
Carry out according to the governing principle of mentioning in " chemicals pungency, anaphylaxis and the hemolytic investigative technique governing principle " that come into force in March, 2005, its key step and condition are with embodiment 1, difference is: in negative control and positive control, the volume ratio of erythrocyte suspension and physiological saline or deionized water is 1:1, correspondingly, the physiological saline in tested property management is also adjusted to corresponding volume.Specifically as shown in table 5:
Table 5
| Test tube numbering | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 2% red cell suspension (ml) | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 |
| Physiological saline (ml) | 2.0 | 2.1 | 2.2 | 2.3 | 2.4 | 2.5 | ? |
| Distilled water (ml) | ? | ? | ? | ? | ? | ? | 2.5 |
| Tested material (ml) | 0.5 | 0.4 | 0.3 | 0.2 | 0.1 | ? | ? |
Hatch after 3 hours, adopt ADVIA2120 type automatic blood analyzer to detect erythrocytic number in positive control pipe.Found that: No. 7 pipe (positive control pipe) still residual red blood cells, haemolysis is incomplete, and its Cytometric concrete outcome is in table 6.
Table 6
The presentation of results of embodiment 1 and comparative example 1, in existing detection method, the haemolysis of its positive control is also incomplete, and therefore such detection system is rational not, can cause the inaccurate of testing result; Method of the present invention haemolysis is complete, thereby makes detection system more reliable, guarantees the accuracy of testing result.
Comparative example 2
Its key step and condition are with embodiment 1, and difference is: in negative control and positive control, the volume ratio of erythrocyte suspension and physiological saline or deionized water is 1:1.1, and correspondingly, the physiological saline in tested property management is also adjusted to corresponding volume.Specifically as shown in table 7:
Table 7
| Test tube numbering | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 2% red cell suspension (ml) | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 |
| Physiological saline (ml) | 2.25 | 2.35 | 2.45 | 2.55 | 2.65 | 2.75 | ? |
| Distilled water (ml) | ? | ? | ? | ? | ? | ? | 2.75 |
| Tested material (ml) | 0.5 | 0.4 | 0.3 | 0.2 | 0.1 | ? | ? |
Hatch after 3 hours, adopt ADVIA2120 type automatic blood analyzer to detect erythrocytic number in positive control pipe.Found that: No. 7 pipe (positive control pipe) still residual red blood cells, haemolysis is incomplete, and its Cytometric concrete outcome is in table 8.
Table 8
| Test tube numbering | 6 | 7 |
| 2% red cell suspension (ml) | 2.5 | 2.5 |
| Physiological saline (ml) | 2.75 | ? |
| Deionized water (ml) | 0 | 2.75 |
| Red blood cell count(RBC) (10 12/L) | 0.09 | 0.03 |
Claims (7)
1. a detection method for the external hemolytic of chemicals, is characterized in that, it comprises the steps:
(1) after adding successively erythrocyte suspension and physiological saline in tested material sample, mix, get the potpourri of erythrocyte suspension and physiological saline as negative control simultaneously, get the potpourri of erythrocyte suspension and deionized water as positive control;
Under (2) 37 DEG C ± 0.5 DEG C environment, hatch and observe;
Wherein, in step (1), in the operation at the described potpourri of getting erythrocyte suspension and physiological saline as negative control, the volume ratio of described erythrocyte suspension and described physiological saline is 1: 1.25～1.3; In operation at the described potpourri of getting erythrocyte suspension and deionized water as positive control, the volume ratio of described erythrocyte suspension and described deionized water is 1: 1.25～1.3.
2. the detection method of the external hemolytic of chemicals as claimed in claim 1, it is characterized in that, in step (1), in described adding successively in the operation mixing after erythrocyte suspension and physiological saline in tested material sample, described tested material sample comprises 5 volumes, be respectively X, 2X, 3X, 4X and 5X, the volume of described physiological saline respectively is 30.25X, 29.25X, 28.25X, 27.25X and 26.25X, and the volume of described erythrocyte suspension is 25X; In operation at the described potpourri of getting erythrocyte suspension and physiological saline as negative control, the volume of described erythrocyte suspension is 25X, and the volume of described physiological saline is 31.25X; In operation at the described potpourri of getting erythrocyte suspension and deionized water as positive control, the volume of described erythrocyte suspension is 25X, and the volume of described deionized water is 31.25X, and described X is any specific volume.
3. the detection method of the external hemolytic of chemicals as claimed in claim 1, is characterized in that, in step (1), the concentration of described erythrocyte suspension is 2%, and described number percent is the percent by volume that blood accounts for erythrocyte suspension.
4. the detection method of the external hemolytic of chemicals as claimed in claim 3, is characterized in that, described erythrocyte suspension is the erythrocyte suspension of taking from rabbit.
5. the detection method of the external hemolytic of chemicals as claimed in claim 1, is characterized in that, in step (1), and the sodium-chloride water solution that described physiological saline is 0.9%.
6. the detection method of the external hemolytic of chemicals as claimed in claim 1, is characterized in that, in step (2), described incubation temperature is 37 DEG C.
7. the detection method of the external hemolytic of chemicals as claimed in claim 1, is characterized in that, in step (2), described being viewed as at the 1st hour that hatches every 15 minutes observed 1 time, after 1 hour, observes 1 time every 1 hour.
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| CN112899217A (en) * | 2021-01-29 | 2021-06-04 | 江西中医药大学 | Medicated liver incubation liquid pharmacologic method and preparation method of medicated liver incubation liquid of ephedra, apricot kernel, gypsum and licorice decoction |
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Address after: 201203 Shanghai City, Pudong New Area Zhangjiang hi tech GuoShouJing Road No. 199 Patentee after: Shanghai Yinuosi biotechnology Limited by Share Ltd Address before: 201203 Shanghai City, Pudong New Area Zhangjiang hi tech GuoShouJing Road No. 199 Patentee before: Shanghai Innostar Bio-tech Co., Ltd. |